Abstract
1. The cytochrome P450 monooxygenases, CYP2D6, CYP2C19, and CYP2C9, display polymorphism. CYP2D6 and CYP2C19 have been studied extensively, and despite their low abundance in the liver, they catalyze the metabolism of many drugs.
2. CYP2D6 has numerous allelic variants, whereas CYP2C19 has only two. Most variants are translated into inactive, truncated protein or fail to express protein.
3. CYP2C9 is expressed as the wild-type enzyme and has two variants, in each of which one amino acid residue has been replaced.
4. The nucleotide base sequences of the cDNAs of the three polymorphic genes and their variants have been determined, and the proteins derived from these genes have been characterized.
5. An absence of CYP2D6 and/or CYP2C19 in an individual produces a poor metabolizer (PM) of drugs that are substrates of these enzymes.
6. When two drugs that are substrates for a polymorphic CYP enzyme are administered concomitantly, each will compete for that enzyme and competitively inhibit the metabolism of the other substrate. This can result in toxicity.
7. Patients can be readily phenotyped or genotyped to determine their CYP2D6 or CYP2C19 enzymatic status. Poor metabolizers (PMs), extensive metabolizers (EMs), and ultrarapid metabolizers (URMs) can be identified.
8. Numerous substrates and inhibitors of CYP2D6, CYP2C19, and CYP2C9 are identified.
9. An individual's diet and age can influence CYP enzyme activity.
10. CYP2D6 polymorphism has been associated with the risk of onset of various illnesses, including cancer, schizophrenia, Parkinson's disease, Alzheimer's disease, and epilepsy.
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REFERENCES
Agúndez, J. A., Martinez, C., Ledesma, M. C., Ladona, M. G., Ladero, J. M., and Benitez, J. (1994). Genetic basis for differences in debrisoquin polymorphism between a Spanish and other white populations. Clin. Pharmacol. Ther. 55:412–417.
Agúndez, J. A., Ledesma, M. C., Ladero, J. M., and Benitez, J. (1995a). Prevalence of CYP2D6 gene duplication and its repercussion on the oxidative phenotype in a white population. Clin. Pharmacol. Ther. 57:265–269.
Agúndez, J. A., Jiménéz-Jimenez, F. J., Luengo, A., Bernal, M. L., Molina, J. A., Ayuso, L., Vazquez, A., Parra, J., Duarte, J., Coria, F., Ladero, J. M., Alvarez, J. C., and Benítez, J. (1995b). Association between the oxidative polymorphism and early onset of Parkinson's disease. Clin. Pharmacol. Ther. 57:291–298.
Allen, J. J., Rack, P. H., and Vaddadi, K. S. (1977). Differences in the effects of clomipramine on English and Asian volunteers: Preliminary report on a pilot study. Postgrad. Med. J. 53:79–86.
Alván, G., Grind, M., Graffner, C., and Sjövist, F. (1984). Relationship of N-demethylation of amiflamine and its metabolite to debrisoquine hydroxylation polymorphism. Clin. Pharmacol. Ther. 36:515–519.
Alván, G., Bechtel, P., Iselius, L., and Gundert-Remy, U. (1990). Hydroxylation polymorphisms of debrisoquine and mephenytoin in European populations. Eur. J. Clin. Pharmacol. 39:533–537.
Anderson, K. E. (1988). Influence of diet and nutrition on clinical pharmacokinetics. Clin. Pharmacokinet 14:325–346.
Andersson, T., Miners, J. O., Veronese, M. E., and Birkett, D. J. (1994). Diazepam metabolism by human liver microsomes is mediated by both S-mephenytoin hydroxylase and CYP3A isoforms. Br. J. Clin. Pharmacol. 38:131–137.
Andreassen, O. A., MacEwan, T., Gulbrandsen, A. K., McCreadie, R. G., and Steen, V. M. (1997). Nonfunctional CYP2D6 alleles and risk for neuroleptic-induced movement disorders in schizophrenic patients. Psychopharmacol. 131:174–179.
Armstrong, M., Daly, A. K., Cholerton, S., Bateman, D. N., and Idle, J. R. (1992). Mutant debrisoquine hydroxylation genes in Parkinson's disease. Lancet 339:1017–1018.
Armstrong, M., Fairbrother, K., Idle, J. R., and Daly, A. K. (1994). The cytochrome P450 CYP2D6 allelic variant CYP2D6J and related polymorphisms in a European population. Pharmacogenetics 4:73–81.
Arthur, H., Dahl, M. L., Siwers, B., and Sjöqvist, F. (1995). Polymorphic drug metabolism in schizophrenic patients with tardive dyskinesia. J. Clin. Psychopharmacol. 15:211–216.
Balant-Gorgia, A. E., Balant, L. P., Genet, C., Dayer, P., Aeschliman, J. M., and Garrone, G. (1986). Importance of oxidative polymorphism and levomepromazine treatment on the steady-state blood concentrations of clomipramine and its major metabolites. Eur. J. Clin. Pharmacol. 31:449–455.
Balant-Gorgia, A. E., Gex-Fabry, M., and Balant, L. P. (1991). Clinical pharmacokinetics of clomipramine. Clin. Pharmacokinet. 20:447–462.
Balian, J. D., Sukhova, N., Harris, J. W., Hewett, J., Pickle, L., Goldstein, J. A., Woosley, R. L., and Flockhart, D. A. (1995). The hydroxylation of omeprazole correlates with S-mephenytoin metabolism: A population study. Clin. Pharmacol. Ther. 57:662–669.
Barbhaiya, R. H., Buch, A. B., and Greene, D. S. (1996). Single and multiple dose pharmacokinetics of nefazodone in subjects classified as extensive and poor metabolizers of dextromethorphan. Br. J. Clin. Pharmacol. 42:573–581.
Bergstrom, R. F., Peyton, A. L., and Lemberger, L. (1992). Quantification and mechanism of the fluoxetine and tricyclic antidepressant interaction. Clin. Pharmacol. Ther. 51:239–248.
Bertilsson, L. (1995). Geographical/interracial differences in polymorphic drug oxidation. Clin. Pharmacokinet 29:192–209.
Bertilsson, L., and Dahl, M. L. (1996). Polymorphic drug oxidation. Relevance to the treatment of psychiatric disorders. CNS Drugs 5:200–223.
Bertilsson, L., Mellström, B., Sjövist, F., Martenson, B., and Asberg, M. (1981). Slow hydroxylation of nortriptyline and concomitant poor debrisoquine hydroxylation: Clinical implications (letter). Lancet 1:560–561.
Bertilsson, L., Henthorn, T. K., Sanz, E., Tybring, G., Säwe, J., and Villen, T. (1989a). Importance of genetic factors in the regulation of diazepam metabolism: Relationship to S-mephenytoin, but not debrisoquin, hydroxylation phenotype. Clin. Pharmacol. Ther. 45:348–355.
Bertilsson, L., Alm, C., De Las Carreras, C., Widen, J., Edman, G., and Schalling, D. (1989b). Debrisoquine hydroxylation polymorphism and personality. Lancet 1:555.
Bertilsson, L., Lou, Y.-Q., Du, Y.-L., Liu, Y., Kuang, T.-Y., Liao, X.-M., Wang, K.-Y., Reviriego, J., Iselius, L., and Sjöqvist, F. (1992). Pronounced differences between native Chinese and Swedish populations in the polymorphic hydroxylations of debrisoquine and S-mephenytoin. Clin. Pharmacol. Ther. 51:388–397.
Berilsson, L., Dahl, M. L., and Tybring, G. (1997). Pharmacogenetics of antidepressants: clinical aspects. Acta Psychiatr. Scand. 391:14–21.
Beyeler, C., Armstrong, M., Bird, H. A., Idle, J. R., and Daly, A. K. (1996). Relationship between genotype for the cytochrome P450 CYP2D6 and susceptibility to ankylosing spondylitis and rheumatoid arthritis. Ann. Rheum. Dis. 55:66–68.
Bloomer, J. C., Woods, F. R., Haddock, R. E., Lennard, M. S., and Tucker, G. T. (1992). The role of cytochrome P4502D6 in the metabolism of paroxetine by human liver microsomes. Br. J. Clin. Pharmacol. 33:521–523.
Bluhm, R. E., Wilkinson, G. R., Shelton, R., and Branch, R. A. (1993). Genetically determined drug-metabolizing activity and desipramine-associated cardiotoxicity: A case report. Clin. Pharmacol. Ther. 53:89–95.
Bolaji, O. O., Coutts, R. T., and Baker, G. B. (1993). Metabolism of trimipramine in vitro by human CYP2D6 isozymes. Res. Commun. Chem. Pathol. Pharmacol. 82:111–120.
Borlak, J. T., Harsany, V., Schneble, H., and Haegele, K. D. (1994). pNAT and CYP2D6 gene polymorphism in epileptic patients. Biochem. Pharmacol. 48:1717–1720.
Breyer-Pfaff, U., Pfandl, B., Nill, K., Nusser, E., Monney, C., Jonzier-Percy, M., Baettig, D., and Baumann, P. (1992). Enantioselective amitriptyline metabolism in patients phenotyped for two cytochrome P450 isozymes. Clin. Pharmacol. Ther. 52:350–358.
Broly, F., Gaedigk, A., Heim, M., Eichelbaum, M., Morike, K., and Meyer, U. A. (1991). Debrisoquine/sparteine hydroxylation genotype and phenotype: Analysis of common mutations and alleles of CYP2D6 in a European population. DNA Cell Biol. 10:545–558.
Brøsen, K. (1990). Recent developments in hepatic drug oxidation—Implications for clinical pharmacokinetics. Clin. Pharmacokinet. 18:220–239.
Brøsen, K., and Gram, L. F. (1988). First-pass metabolism of imipramine and desipramine: Impact of the sparteine oxidation phenotype. Clin. Pharmacol. Ther. 43:400–406.
Brøsen, K., Zeugin, T., and Meyer, U. A. (1991). Role of P450IID6, the target of the sparteine-debrisoquin oxidation polymorphism, in the metabolism of imipramine. Clin. Pharmacol. Ther. 49:609–617.
Brøsen, K., Hansen, J. G., Nielsen, K. K., Sindrup, S. H., and Gram, L. F. (1993). Inhibition by paroxetine of desipramine metabolism in extensive but not in poor metabolizers of sparteine. Eur. J. Clin. Pharmacol. 44:349–355.
Chiba, K., Saitoh, A., Koyama, E., Tani, M., Hayashi, M., and Ishizaki, T. (1994). The role of Smephenytoin 4′-hydroxylase in imipramine metabolism by human liver microsomes: A two-enzyme kinetic analysis of N-demethylation and 2-hydroxylation. J. Clin. Pharmacol. 37:237–242.
Ching, M. S., Blake, C. L., Ghabrial, H., Ellis, S. W., Lennard, M. S., Tucker, G. T., and Smallwood, R. A. (1995). Potent inhibition of yeast-expressed CYP2D6 by dihydroquinidine, quinidine, and its metabolites. Biochem Pharmacol 50:833–837.
Choo, H. Y., Shin, Y. O., and Park, J. (1990). Study of the metabolism of phenothiazines: Determination of N-demethylated phenothiazines in urine. J. Anal. Toxicol. 14:116–119.
Christensen, P. M., Gotzsche, P. C., and Brøsen, K. (1997). The sparteine/debrisoquine (CYP2D6) oxidation polymorphism and the risk of lung cancer: A meta analysis. Eur. J. Clin. Pharmacol. 51:389–393.
Coleman, T., Ellis, S. W., Martin, I. J., Lennard, M. S., and Tucker, G. T. (1996). 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is N-emethylated by cytochromes P450 2D6, 1A2 and 3A4—implications for susceptibility to Parkinson's disease. J. Pharmacol. Exp. Ther. 277:685–690.
Coutts, R. T. (1994). Polymorphism in the metabolism of drugs, including antidepressant drugs: Comments on phenotyping. J. Psychiatr Neurosci. 19:30–44.
Coutts, R. T., Su, P., and Baker, G. B. (1994). Involvement of CYP2D6, CYP3A4 and other cytochrome P-450 isozymes in N-dealkylation reactions. J. Pharmacol. Toxicol. Methods 31:177–186.
Coutts, R. T., Bach, M. V., and Baker, G. G. (1997). Metabolism of amitriptyline with CYP2D6 expressed in a human cell line. Xenobiotica 26:33–47.
Crespi, C. L., Steimel, D. T., Penman, B. W., Korzekwa, K. R., Fernandez-Salguero, P., Buters, J. T., Gelboin, H. V., Gonzalez, F. J., Idle, J. R., and Daly, A. K. (1995). Comparison of substrate metabolism by wild type CYP2D6 protein and a variant containing methionine, not valine, at position 374. Pharmacogenetics 5:234–243.
Crewe, H. K., Lennard, M. S., Tucker, G. T., Woods, F. R., and Haddock, R. E. (1992). The effect of selective serotonin re-uptake inhibitors on cytochrome P4502D6 (CYP2D6) activity in human liver microsomes. Br. J. Clin. Pharmacol. 34:262–265.
Dahl, M. L., Johansson, J., Palmertz, M. P., Ingleman-Sundberg, M., Sjövist, F. (1992). Analysis of the CYP2D6 gene in relation to debrisoquin and desipramine hydroxylation in a Swedish population. Clin. Pharmacol. Ther. 51:12–17.
Dahl, M. L., Tybring, G., Elwin, C. E., Alm, C., Andreasson, K., Gyllenpalm, M., and Bertilsson, L. (1994). Stereoselective disposition of mianserin is related to debrisoquin hydroxylation polymorphism. Clin. Pharmacol. Ther. 56:176–183.
Dahl, M. L., Yue, Q.-Y., Roh, H.-K., Johansson, I., Säwe, J., Sjövist, F., and Bertilsson, L. (1995). Genetic analysis of the CYP2D locus in relation to debrisoquine hydroxylation capacity in Korean, Japanese and Chinese subjects. Pharmacogenetics 5:159–164.
Dahl-Puustinen, M. L., Lidén, A., Alm, C., Nordin, C., and Bertilsson, L. (1989). Disposition of perphenazine is related to polymorphic debrisoquin hydroxylation in human beings. Clin. Pharmacol. Ther. 46:78–81.
Daly, A. K., Armstrong, M., Monkman, S. C., Idle, M. E., and Idle, J. R. (1991). Genetic and metabolic criteria for the assignment of debrisoquine 4-hydroxylation (cytochrome P4502D6) phenotypes. Pharmacogenetics 1:33–41.
Daly, A. K., Leathart, J. B., London, S. J., and Idle, J. R. (1995). An inactive cytochrome P450 CYP2D6 allele containing a deletion and a base substitution. Hum. Genet. 95:337–341.
Daniels, J., Williams, J., Asherson, P., McGuffin, P., and Owen, M. (1995). No association between schizophrenia and polymorphisms within the genes for debrisoquine 4-hydroxylase (CYP2D6) and the dopamine transporter (DAT). Am. J. Med. Genet. 60:85–87.
Dawson, E., Powell, J. F., Nothen, M. M., Crocq, M. A., Lanczik, M., Korner, J., Rietschel, M., van Os, J., Wright, P., and Gill, M. (1994). An association study of debrisoquine hydroxylase (CYP2D6) polymorphisms in schizophrenia. Psychiatr. Genet. 4:215–218.
de Groot, M. J., Bijloo, G. J., Martens, B. J., van Acker, F. A., and Vermeulen, N. P. (1997). A refined substrate model for human cytochrome P450 2D6. Chem. Res. Toxicol. 10:41–48.
Degtyarenko, K. N., and Fabian, P. (1996). The directory of P450-containing systems on WorldWide Web. Comput. Appl Biosci. 12:237–240.
de Morais, S. M., Wilkinson, G. R., Blaisdell, J., Nakamura, K., Meyer, U. A., and Goldstein, J. A. (1994a). The major genetic defect responsible for the polymorphism of S-mephenytoin metabolism in humans. J. Biol. Chem. 269:15419–15422.
de Morais, S. M., Wilkinson, G. R., Blaisdell, J., Meyer, U. A., Nakamura, K., and Goldstein, J. A. (1994b). Identification of a new genetic defect responsible for the polymorphism of (S)mephenytoin metabolism in Japanese. Mol. Pharmacol. 46:594–598.
Dollery, C., Fraser, H., and Mucklow, J. (1979). Contribution of environmental factors to variability in human drug metabolism. Drug Metab. Rev. 9:207–220.
Eap, C. B., Guentert, T. W., Schaublin-Loidl, M., Stabl, M., Koeb, L., Powell, K., and Baumann, P. (1996). Plasma levels of the enantiomers of thioridazine, thioridazine 2-sulfoxide, thioridazine 2-sulfone, and thioridazine 5-sulfoxide in poor and extensive metabolizers of dextromethorphan and mephenytoin. Clin. Pharmacol. Ther. 59:322–331.
Ellis, S. W., Rowland, K., Ackland, M. J., Rekka, E., Simula, A. P., Lennard, M. S., Wolf, C. R., and Tucker, G. T. (1996). Influence of amino acid residue 374 of cytochrome P-450 2D6 (CYP2D6) on the regio-and enantio-selective metabolism of metoprolol. Biochem. J. 316:647–654.
Evans, W. E., and Relling, M. V. (1991). Concordance of P450 2D6 (debrisoquine hydroxylase) phenotype and genotype: Inability of dextromethorphan metabolic ratio to discriminate reliably heterozygous and homozygous extensive metabolizers. Pharmacogenetics 1:143–148.
Evans, W. E., Relling, M. V., Rahman, A., Mcleod, H. L., Scott, E. P., and Lin, J. S. (1993). Genetic basis for a lower prevalence of deficient CYP2D6 oxidative drug metabolism phenotypes in black Americans. J. Clin. Invest. 91:2150–2154.
Evert, B., Griese, E. U., and Eichelbaum, M. (1994). A missense mutation in exon 6 of the CYP2D6 gene leading to a histidine 324 to proline exchange is associated with the poor metabolizer phenotype of sparteine. Naunyn-Schmiedebergs Arch. Pharmacol. 350:434–439.
Fang, J., Baker, G. B., Silverstone, P. H., and Coutts, R. T. (1997). Involvement of CYP3A4 and CYP2D6 in the metabolism of haloperidol. Cell Mol. Neurobiol. 17:227–233.
Feher, M. D., Lucas, R. A., Farid, N. A., Idle, J. R., Bergstrom, R. F., Lemberger, L., and Sever, P. S. (1988). Single dose pharmacokinetics of tomoxetine in poor and extensive metabolisers of debrisoquine. Proc. BPS.
Feifel, N., Kuchner, K., Fuchs, L., Jedrychowski, M., Schmidt, E., Antonin, K.-H, Bieck, P. R., and Gleiter, C. H. (1993). Role of cytochrome P4502D6 in the metabolism of brofaromine. A new selective MAO-A inhibitor. Eur. J. Clin. Pharmacol. 45:265–269.
Firkusny, L., and Gleiter, C. H. (1994). Maprotiline metabolism appears to cosegregate with the genetically determined CYP2D6 polymorphic hydroxylation of debrisoquine. Br. J. Clin. Pharmacol. 37:383–388.
Fischer, V., Vogels, B., Maurer, G., and Tynes, R. E. (1992). The antipsychotic clozapine is metabolized by the poymorphic human microsomal and recombinant cytochrome P450 2D6. J. Pharmacol. Exp. Ther. 260:1355–1360.
Fischer, V., Vickers, A. E. M., Heitz, F., Mahadevan, S., Baldeck, J.-P., Minery, P., and Tynes, R. (1994). The polymorphic cytochrome P-4502D6 is involved in the metabolism of both 5-hydroxytryptamine antagonists, tropisetron and ondansetron. Drug. Metab. Disp. 22:269–274.
Fraser, H., Mucklow, J., Bulpitt, C., Kahn, C., Mould, G., and Dollery, C. (1979), Environmental factors affecting antipyrine metabolism in London factory and office workers. Br. J. Clin. Pharmacol. 7:237–243.
Gaedigk, A., Blum, M., Gaedigk, R., Eichelbaum, M., and Meyer, U. A. (1991). Deletion of the entire cytochrome P450 CYP2D6 gene as a cause of impaired drug metabolism in poor metabolizers of the debrisoquine/ sparteine polymorphism. Am. J. Hum. Genet. 48:943–950.
Gasser, T., Wszolek, Z. K., Trofatter, J., Ozelius, L., Uitti, R. J., Lee, C. S., Gusella, J., Pfeiffer, R. F., Calne, D. B., and Breakefield, X. O. (1994). Genetic linkage studies in autosomal dominant parkinsonism: Evaluation of seven candidate genes. Ann. Neurol. 36:387–396.
Goldstein, J. A., Faletto, M. B., Romkes-Sparks, M., Sullivan, T., Kitareewan, S., Raucy, J. L., Lasker, J. M., and Ghanayem, B. I. (1994). Evidence that CYP2C19 is the major (S)-mephenytoin 4′-hydroxylase in humans. Biochemistry 33:1743–1752.
Gonzalez, F. J., and Idle, J. R. (1994). Pharmacogenetic phenotyping and genotyping. Present status and future potential. Clin. Pharmacokinet. 26:59–70.
Gonzalez, F. J., and Meyer, U. A. (1991). Molecular genetics of the debrisoquin-sparteine polymorphism. Clin. Pharmacol. Ther. 50:233–238.
Gonzalez, F. J., Nebert, D. W. (1990). Evolution of the P450 gene superfamily: Animal-plant “warfare,” molecular drive and human genetic differences in drug oxidation. Trends Genet. 6:182–186.
Gonzalez, F. J., Skoda, R. C., Kimura, S., Umeno, M., Zanger, U. M., Nebert, D. W., Gelboin, H. V., Hardwick, J. P., and Meyer, U. A. (1988). Characterization of the common genetic defect in humans deficient in debrisoquine metabolism. Nature 331:442–446.
Gonzalez, F. J., Vilbois, F., Hardwick, J. P., McBride, O. W., Nebert, D. W., Gelboin, H. V., and Meyer, U. A. (1991). Human debrisoquine 4-hydroxylase (P450IID1):cDNA and deduced amino acid sequence and assignment of the CYP2D locus to chromosome 22. Genomics 2:174–179.
Grace, J. M., Kinter, M. T., and Macdonald, L. (1994). Atypical metabolism of deprenyl and its enantiomer, (S)-(+)-N,α-dimethyl-N-propynylphenethylamine, by cytochrome P450 2D6. Chem. Res. Tox. 7:286–290.
Gram, L. F., and Overo, K. F. (1972). Drug interaction: Inhibitory effect of neuroleptics on metabolism of tricyclic antidepressants in man. Br. Med. J. 1:463–465.
Gram, L. F., Overo, K., Kirk, L. (1974). Influence of neuroleptics and benzodiazepines on metabolism of tricyclic antidepressants in man. Am. J. Psychiatry 131:863–866.
Gram, L. F., Guentert, T. W., Grange, S., Vistisen, K., and Brøsen, K. (1995). Moclobemide, a substrate of CYP2C19 and an inhibitor of CYP2C19, CYP2D6, and CYP1A2: A panel study. Clin. Pharmacol. Ther. 57:670–677.
Gray, I. C., Nobile, C., Muresu, R., Ford, S., and Spurr, N. K. (1995). A 2.4-megabase physical map spanning the CYP2C gene cluster on chromosome 10q24. Genomics 28:328–332.
Greenblatt, D. J., Sellers, E. M., and Shader, R. I. (1982). Drug disposition in old age. N. Engl. J. Med. 306:1081–1088.
Guengerich, F. P. (1988). Role of cytochrome P-450 enzymes in chemical carcinogenesis and cancer chemotherapy. Cancer Res. 48:2946–2954.
Guengerich, F. P. (1995). Human cytochrome P-450 enzymes. In Ortiz de Montellano, P. R. (ed.), Cytochrome P-450, 2nd ed., Plenum Press, New York.
Guengerich, F. P., Distlerath, L. M., Reilly, P. E. B., Wolff, T., Shimada, T., Umbenhauer, D. R., and Martin, M. V. (1986). Human-liver cytochromes P-450 involved in polymorphisms of drug oxidation. Xenobiotica 16:367–378.
Haining, R. L., Hunter, A. P., Veronese, M. E., Trager, W. F., and Rettie, A. E. (1996). Allelic variants of human cytochrome P450 2C9: Baculovirus-mediated expression, purification, structural characterization, substrate stereoselectivity, and prochiral selectivity of the wild-type and I359L mutant forms. Arch. Biochem. Biophys. 333:447–458.
Harvey, A. T., and Preskorn, S. H. (1996). Cytochrome P450 enzymes: Interpretation of their interactions with selective serotonin reuptake inhibitors. Part 1. J. Clin. Psychopharmacol 16:273–285.
Heim. M. H., and Meyer, U. A. (1991). Genetic polymorphism of debrisoquine oxidation: Restriction fragment analysis and allele-specific amplification of mutant alleles of CYP2D6. Methods Enzymol 206:173–183.
Heim, M. H., and Meyer, U. A. (1992). Evolution of a highly polymorphic human cytochrome P450 gene cluster: CYP2D6. Genomics 14:49–58.
Henthorn, T. K., Benitez, J., Avram, M. J., Martinez, C., Llerena, A., Cobaleda, J., Krejcie, T. C., and Gibbons, R. D. (1989). Assessment of the debrisoquin and dextromethorphan phenotyping tests by gaussian mixture distributions analysis. Clin. Pharmacol. Ther. 45:328–333.
Horai, Y., Nakano, M., Ishizaki, T., Ishikawa, K., Zhou, H.-H., Zhou, B.-J., Liao, C.-L., and Zhang, L.-M. (1989). Metoprolol and mephenytoin oxidation polymorphisms in Far Eastern Oriental subjects: Japanese versus mainland Chinese. Clin. Pharmacol. Ther. 46:198–207.
Ieiri, I., Kubota, T., Urae, A., Kimura, M., Wada, Y., Mamiya, K., Yoshioka, S., Irie, S., Amamoto, T., Nakamura, K., Nakano, S., and Higuchi, S. (1996). Pharmacokinetics of omeprazole (a substrate of CYP2C19) and comparison with two mutant alleles, CYP2C19m1 in exon 5 and CYP2C19m2 in exon 4, in Japanese subjects. Clin. Pharmacol. Ther. 59:647–653.
Inaba, T., Jurima, M., Mahon, W. A., and Kalow, W. (1985). In vitro inhibition studies of two isozymes of human liver cytochrome P-450: Mephenytoin p-hydroxylase and sparteine monooxygenase. Drug. Metab. Disp. 13:443–448.
James, O. F. W., Rawlins, M. D., and Woodhouse, K. (1982). Lack of ageing effect on human microsomal monooxygenase enzyme activities and on inactivation pathways for reactive metabolic intermediates. In Kitani, K. (ed.), Liver and Ageing, Elsevier, Amsterdam, pp. 395–406.
Jerling, M., Dahl, M. L., Aberg-Wistedt, A., Liljenberg, B., Landell, N. E., Bertilsson, L., and Sjövist, F. (1996). The CYP2D6 genotype predicts the oral clearance of the neuroleptic agents perphenazine and zuclopenthixol. Clin. Pharmacol. Ther. 59:423–428.
Johansson, I., Yue, Q. Y., Dahl, M. L., Heim, M., Säwe, J., Bertilsson, L., Meyer, U. A., Sjöqvist, F., and Ingelman-Sundberg, M. (1991). Genetic analysis of the interethnic difference between Chinese and Caucasians in the polymorphic metabolism of debrisoquine and codeine. Eur. J. Clin. Pharmacol. 40:553–556.
Johansson, I., Oscarsson, M., Yue, Q. Y., Bertilsson, L., Sjöqvist, F., and Ingelman-Sundberg, M. (1994). Genetic analysis of the Chinese cytochrome P4502D locus: characterization of variant CYP2D6 genes present in subjects with diminished capacity for debrisoquine hydroxylation. Mol. Pharmacol. 46:452–459.
Jurima, M., Inaba, T., Kadar, D., and Kalow, W. (1985). Genetic polymorphism of mephenytoin p(4′)hydroxylation: Difference between Orientals and Caucasians. Br. J. Clin. Pharmacol. 19:483–487.
Kagimoto, M., Heim, M., Kagimoto, K., Zeugin, T., and Meyer, U. A. (1990). Multiple mutations of the human cytochrome P450IID6 gene (CYP2D6) in poor metabolizers of debrisoquine. J. Biol. Chem. 265:17209–17214.
Kalow, W., and Tyndale, R. F. (1992). Debrisoquine/sparteine monooxygenase and other P-450s in brain. In Kalow, W. (ed.), Pharmacogenetics of Drug Metabolism: International Encyclopedia of Pharmacology and Therapeutics, Pergamon Press, New York, pp. 649–656.
Kapitany, T., Meszaros, K., Lenzinger, E., Schindler, S. D., Barnas, C., Fuchs, K., Sieghart, W., Aschauer, H. N., and Kasper, S. (1998). Genetic polymorphisms for drug metabolism (CYP2D6) and tardive dyskinesia in schizophrenia. Schizo. Res. 32:101–106.
Klamerus, K. J., Maloney, K., Rudolph, R. L., Sisenwine, S. F., Jusko, W. J., and Chiang, S. T. (1992). Introduction of a composite parameter to the pharmacokinetics of venlafaxine and its active O-desmethyl metabolite. J. Clin. Pharmacol. 32:716–724.
Kondo, I., and Kanazawa, I. (1993). Debrisoquine hydroxylase and Parkinson's disease. Adv. Neurol. 60:338–342.
Kroemer, H. K., and Eichelbaum, M. (1995). “It's the genes, stupid.” Molecular bases and clinical consequences of genetic cytochrome P450 2D6 polymorphism. Life Sci. 56:2285–2298.
Küpfer, A., and Preisig, R. (1984). Pharmacogenetics of mephenyton:Anew drug hydroxylation polymorphism in man. Eur. J. Clin. Pharmacol. 26:753–759.
Küpfer, A., Desmond, P., Schenker, S., and Branch, R. (1979). Family study of a genetically determined deficiency of mephenytoin hydroxylation in man. Pharmacologist 21:173 (abstract 160).
Küpfer, A., Lawson, J., and Branch, R. A. (1984a). Stereoselectivity of the arene epoxide pathway of mephenytoin hydroxylation in man. Epilepsia 25:1–7.
Küpfer, A., Desmond, P., Patwardhan, R., Schenker, S., and Branch, R. A. (1984b). Mephenytoin hydroxylation deficiency: Kinetics after repeated doses. Clin. Pharmacol. Ther. 35:33–39.
Kurth, M. C., and Kurth, J. H. (1993). Variant cytochrome P450 CYP2D6 allelic frequencies in Parkinson's disease. Amer. J. Med. Genet. 48:166–168.
Landi, M. T., Ceroni, M., Martignoni, E., Bertazzi, P. A., Caporaso, N. E., and Nappi, G. (1996). Gene-environment interaction in parkinson's disease. The case of CYP2D6 gene polymorphism. Adv. Neurol. 69:61–72.
Lee, E. J., and Jeyaseelan, K. (1994). Frequency of human CYP2D6 mutant alleles in a normal Chinese population. Br. J. Clin. Pharmacol. 37:605–607.
Lewis, P., Rack, P., and Vaddadi, K. (1980). Ethnic differences in drug response. Postgrad. Med. J. 56(Suppl. 1):46–49.
Lin, C., Hahnenberger, K. M., Cronin, M. T., Lee, D., Sampas, N. M., Kanemoto, R. (1996a). A method for genotyping CYP2D6 and CYP2C19 using oligonucleotide array hybridization. ISSX Proc., San Diego, CA p. 243.
Lin, K.-M., Poland, R. E., Wan, Y.-J.Y., Smith, M. W., and Lesser, I. M. (1996b). The evolving science of pharmacogenetics: Clinical and ethnic perspectives. Psychopharmacol. Bull. 32:205–217.
Llerena, A., Alm, C., Dahl, B., and Bertilsson, L. (1992). Haloperidol disposition is dependent on debrisoquine hydroxylation phenotype. Ther. Drug. Monit. 14:92–97.
Mackman, R., Tschirret-Guth, R. A., Smith, G., Hayhurst, G. P., Ellis, S. W., Lennard, M. S., Tucker, G. T., Wolf, C. R., and Ortiz de Montellano, P. R. (1996). Active-site topologies of human CYP2D6 and its aspartate-301 → glutamate, asparagine, and glycine mutants. Arch. Biochem. Biophys. 331:134–140.
Mahgoub, A., Idle, J. R., Dring, L. G., Lancaster, R., and Smith, R. L. (1977). Polymorphic hydroxylation of debrisoquine in man. Lancet 2:584–586.
Marez, D., Sabbagh, N., Legrand, M., Lo-Guidice, J. M., Boone, P., and Broly, F. (1995). A novel CYP2D6 allele with an abolished splice recognition site associated with the poor metabolizer phenotype. Pharmacogenetics 5:305–311.
Marez, D., Legrand, M., Sabbagh, N., Lo-Guidice, J. M., Boone, P., and Broly, F. (1996). An additional allelic variant of the CYP2D6 gene causing impaired metabolism of sparteine. Hum. Genet. 97:668–670.
Marre, F., Fabre, G., Lacarelle, B., Bourrie, M., Catalin, J., Berger, Y., Rahmani, R., and Cano, J. P. (1992). Involvement of the cytochrome P-450IID subfamily in minaprine 4-hydroxylation by human hepatic microsomes. Drug Metab. Disp. 20:316–321.
Masimirembwa, C., Bertilsson, L., Johansson, I., Hasler, J. A., and Ingelman-Sundberg, M. (1995). Phenotyping and genotyping of S-mephenytoin hydroxylase (cytochrome P450 2C19) in a Shona population of Zimbabwe. Clin. Pharmacol. Ther. 57:656–661.
Masimirembwa, C. M., Johansson, I., Hasler, J. A., and Ingleman-Sundberg, M. (1993). Genetic polymorphism of cytochrome P450 2D6 in a Zimbabwean population. Pharmacogenetics 3:275–280.
Meier, U. T., Kronbach, T., and Meyer, U. A. (1985). Assay of mephenytoin metabolism in human liver microsomes by high-performance liquid chromatograpy. Anal. Biochem. 151:286–291.
Mellström, B., Bertilsson, L., Lou, Y.-C., Säwe, J., and Sjövist, F. (1983). Amitriptyline metabolism: Relationship to polymorphic debrisoquine hydroxylation. Clin. Pharmacol. Ther. 34:516–520.
Meyer, U. A., Amrein, R., Balant, L. P., Bertilsson, L., Eichelbaum, M., Guentert, T. W., Henauer, S., Jackson, P., Laux, G., Mikkelsen, H., Peck, C., Pollock, B. G., Priest, R., Sjöqvist, F., and Delini-Stula, A. (1996). Antidepressants and drug-metabolizing enzymes—expert group report. Acta Psychiatr. Scand. 93:71–79.
Miners, J. O., and Birkett, D. J. (1998). Cytochrome P4502C9: an enzyme of major importance in human drug metabolism. Br. J. Clin. Pharmacol. 45:525–538.
Nakamura, K., Goto, F., Ray, W. A., McAllister, C. B., Jacqz, E., Wilkinson, G. R., and Branch, R. A. (1985). Interethnic differences in genetic polymorphism of debrisoquin and mephenytoin hydroxylation between Japanese and Caucasian populations. Clin. Pharmacol. 38:402–408.
Nelson, D. R., Koymans, L., Kamataki, T., Stegeman, J. J., Feyereisen, R., Waxman, D. J., Waterman, M. R., Gotoh, O., Coon, J., Estabrook, R. W., Gunsalus, I. C., and Nebert, D. W. (1996). P450 superfamily: Update on new sequences, gene mapping, accession numbers and nomenclature. Pharmacogenetics 6:1–42.
Nielsen, K. K., Brøsen, K., Hansen, M. G., and Gram, L. F. (1994). Single-dose kinetics of clomipramine: Relationship to the sparteine and S-mephenytoin oxidation polymorphisms. Clin. Pharmacol. Ther. 55:518–527.
Nielsen, K. K., Flinois, J. P., Beaune, P., and Brøsen, K. (1996). The biotransformation of clomipramine in vitro, identification of the cytochrome P450s responsible for the separate metabolic pathways. J. Pharmacol. Exp. Ther. 277:1659–1664.
Nyberg, S., Dahl, M. L., and Halldin, C. (1995). A PET study of D2 and 5-HT2 receptor occupancy induced by risperidone in poor metabolizers of debrisoquin and risperidone. Psychopharmacology 119:345–348.
Otton, S. V., Ball, S. E., Cheung, S. W., Inaba, T., Rudolph, R. L., and Sellers, E. M. (1996). Venlafaxine oxidation in vitro is catalysed by CYP2D6. Br. J. Clin. Pharmacol. 41:149–156.
Overo, K. F., Gram, L. F., and Hansen, V. (1977). Interaction of perphenazine with the kinetics of nortriptyline. Acta Pharmacol. Toxicol. 40:97–105.
Partovian, C., Jacqz-Aigrain, E., Keundjian, A., Jaillon, P., and Funck-Brentano, C. (1995). Comparison of chloroguanide and mephenytoin for the in vivo assessment of genetically determined CYP2C19 activity in humans. Clin. Pharmacol. Ther. 58:257–263.
Pearce, R. E., Rodrigues, A. D., Goldstein, J. A., and Parkinson, A. (1996). Identification of the human P450 enzymes involved in lansoprazole metabolism. J. Pharmacol. Exp. Ther. 277:805–816.
Perault, M. C., Bouquet, S., Bertschy, G., Vandel, S., Chakroun, R., Guibert, S., and Vandel, B. (1991). Debrisoquine and dextromethorphan phenotyping and antidepressant treatment. Therapie 46:1–3.
Plante-Bordeneuve, V., Bandmann, O., Wenning, G., Quinn, N. P., Daniel, S. E., and Harding, A. E. (1995). CYP2D6-debrisoquine hydroxylase gene polymorphism in multiple system atrophy. Move. Disord. 10:277–278.
Pollock, B. G., Perel, J. M., Kirshner, M., Altieri, L. P., Yeager, A. L., and Reynolds, C. F., III (1991). S-Mephenytoin 4-hydroxylation in older Americans. Eur. J. Clin. Pharmacol. 40:609–611.
Pollock, B. G., Perel, J. M., Altieri, L. P., Kirshner, M., Fasiczka, A. L., Houck, P. R., and Reynolds, C. F., III (1992). Debrisoquine hydroxylation phenotyping in geriatric psychopharmacology. Psychopharmacol Bull. 28:163–168.
Preskorn, S. H., Alderman, J., Chung, M., Harrison, W., Messig, M., and Harris, S. (1994). Pharmacokinetics of desipramine coadministered with sertraline or fluoxetine. J. Clin. Psychopharmacol. 14:90–98.
Price Evans, D. A., Mahgoub, A., Sloan, T. P., Idle, J. R., and Smith, R. L. (1980). Afamily and population study of the genetic polymorphism of debrisoquine oxidation in a white British population. J. Med. Genet. 17:102–105.
Rannug, A., Alexandrie, A. K., Persson, I., and Ingelman-Sundberg, M. (1995). Genetic polymorphism of cytochromes P450 1A1, 2D6 and 2E1: regulation and toxicological significance. J. Occup. Environ. Med. 37:25–36.
Reidenberg, P., Glue, P., Banfield, C. R., Colucci, R. D., Meehan, J. W., Radwanski, E., Mojavarian, P., Lin, C. C., Nezamis, J., Guillaume, M., and Affrime, M. B. (1995). Effects of felbamate on the pharmacokinetics of phenobarbital. Clin. Pharmacol. Ther. 58:279–287.
Rettie, A. E., Wienkers, L. C., Gonzalez, F. J., Trager, W. F., and Korzekwa, K. R. (1994). Impaired (S)-warfarin metabolism catalysed by the R144C allelic varient of CYP2C9. Pharmacogenetics 4:39–42.
Richelson, E. (1997). Pharmacokinetic drug interactions of new antidepressants: a review on the effects on the metabolism of other drugs. Mayo Clin. Proc. 72:835–847.
Riedl, A. G., Watts, P. M., Jenner, P., and Marsden, C. D. (1998). P450 enzymes and Parkinson's disease: the story so far. Mov. Disord. 13:212–220.
Ring, B. J., Catlow, J., Linsay, T. J., Gillespie, T., Roskos, L. K., Cerimele, B. J., Swanson, S. P., Hamman, M. A., and Wrighton, S. A. (1996). Identification of the human cytochromes P450 responsible for the in vitro formation of the major oxidative metabolites of the antipsychotic agent olanzapine. J. Pharmacol. Exp. Ther. 276:658–666.
Rost, K. L., and Roots, I. (1996). Nonlinear kinetics after high-dose omeprazole caused by saturation of genetically variable CYP2C19. Hepatology 23:1491–1497.
Rostami-Hodjegan, A., Lennard, M. S., Woods, H. F., and Tucker, G. T. (1998). Meta-analysis of studies of the CYP2D6 polymorphism in relation to lung cancer and Parkinson's disease. Pharmacogenet. 8:227–238.
Sabbagh, N., Marez, D., Queyrel, V., Lo Guidice, J. M., Spire, C., Vanhille, P., Jorgensen, C., Hachulla, E., and Broly, F. (1998). Genetic analysis of the cytochrome P450 CYP2D6 polymorphism in patients with systemic lupus erythematosus. Pharmacogenet. 8:191–194.
Saitoh, T., Xia, Y., Chen, X., Masliah, E., Galasko, D., Shults, C., Thal, L. J., Hansen, L. A., and Katzman, R. (1995). The CYP2D6B mutant allele is overrepresented in the Lewy body variant of Alzheimer's disease. Ann. Neurol. 37:110–112.
Schellens, J. H. M., van der Wart, J. H., and Breimer, D. D. (1990). Relationship between mephenytoin oxidation polymorphism and phenytoin, methylphenytoin and phenobarbital hydroxylation assessed in a panel of healthy subjects. Br. J. Clin. Pharmacol. 29:665–671.
Schmider, J., Greenblatt, D. J., von Moltke, L. L., Karsov, D., and Shader, R. I. (1997). Inhibition of CYP2C9 by selective serotonin reuptake inhibitors in vitro: studies of phenytoin p-hydroxylation. Br. J. Clin. Pharmacol. 44:495–498.
Shimada, T., Yamazaki, H., Mimura, M., Inui, Y., and Guengerich, F. P. (1994). Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: Studies with liver microsomes of 30 Japanese and 30 Caucasians. J. Pharmacol. Exp. Ther. 270:414–423.
Siegmund, W., Hanke, W., Zschiesche, M., Franke, G., Biebler, K. E., and Wilke, A. (1990). N-Acetylation and debrisoquine type oxidation polymorphism in Caucasians with reference to age and sex. Int. J. Clin. Pharmacol. Ther. Toxicol. 12:504–509.
Sindrup, S. H., Brøsen, K., Gram, L. F., Hallas, J., Skjelbo, E., Allen, A., Allen, G. D., Cooper, S. M., Mellows, G., Tasker, T., and Zussman, B. D. (1992). The relationship between paroxetine and the sparteine oxidation polymorphism. Clin. Pharmacol. Ther. 51:278–287.
Sindrup, S. H., Poulsen, L., Brøsen, K., Arendt-Nielsen, L., and Gram, L. F. (1993a). Are poor metabolisers of sparteine/debrisoquine less pain tolerant than extensive metabolisers? Pain 53:335–339.
Sindrup, S. H., Brøsen, K., Hansen, M. G. J., Aaes-Jorgensen, T., Overo, K. F., and Gram, L. F. (1993b). Pharmacokinetics of citalopram in relation to the sparteine and the mephenytoin oxidation polymorphisms. Ther. Drug Monit. 15:11–17.
Skjelbo E, Br;ol;sen K (1992). Inhibitors of imipramine metabolism by human liver microsomes. Br. J. Clin. Pharmacol. 34:256–261.
Skjelbo, E., Mutabingwa, T. K., Bygbjerg, I., Nielsen, K. K., Gram, L. F., and Brøsen, K. (1996). Chloroguanide metabolism in relation to the efficacy in malaria prophylaxis and the S-mephenytoin oxidation in Tanzanians. Clin. Pharmacol. Ther. 59:304–311.
Smith, C. A. D., Gough, A. C., Leigh, P. N., Summers, B. A., Harding, A. E., Maranganore, D. M., Sturman, S. G., Schapira, A. H. V., Williams, A. C., Spurr, N. K., and Wolf, C. R. (1992). Debrisoquine hydroxylase gene polymorphism and susceptibility to Parkinson's disease. Lancet 339:1375–1377.
Sohn, D.-R., Kusaka, M., Ishizaki, T., Shin, S.-G., Jang, I.-J., Shin, J.-G., and Chiba, K. (1992). Incidence of S-mephenytoin hydroxylation deficiency in a Korean population and the interphenotypic differences in diazepam pharmacokinetics. Clin. Pharmacol. Ther. 52:160–169.
Spina, E., Martines, C., Caputi, A. P., Cobaleda, J., Pinas, B., Carrillo, J. A., and Benitez (1991). Debrisoquine oxidation phenotype during neuroleptic monotherapy. Eur. J. Clin. Pharmacol. 41:467–470.
Su, P., Coutts, R. T., Baker, G. B., and Daneshtalab, M. (1993). Analysis of imipramine and three metabolites produced by isozyme CYP2D6 expressed in a human cell line. Xenobiotica 23:1289–1298.
Tsuneoka, Y., Matsuo, Y., Iwahashi, K., Takeuchi, H., and Ichikawa, Y. (1993). A novel cytochrome P-450IID6 mutant gene associated with Parkinson's disease. J. Biochem. 114:263–266.
Tucker, G. T., Lennard, M. S., Ellis, S. W., Woods, H. F., Cho, A. K., Lin, L. Y., Hiratsuka, A., Schmitz, D. A., and Chu, T. Y. (1994). The demethylation of methylenedioxymethamphetamine (“ecstasy”) by debrisoquine hydroxylase (CYP2D6). Biochem. Pharmacol. 47:1151–1156.
Tyndale, R. F., Sunahara, R., Inaba, T., Kalow, W., Gonzalez, J., and Niznik, H. B. (1991). Neuronal cytochrome P450IID1 (debrisoquine/sparteine-type): Potent inhibition of activity by (−)-cocaine and nucleotide sequence identity to human hepatic P450 gene CYP2D6. Mol. Pharmacol. 40:63–68.
Vandel, S., Bertschy, G., Baumann, P., Bouquet, S., Bonin, B., Francois, T., Sechter, D., and Bizouard, P. (1995). Fluvoxamine and fluoxetine: Interaction studies with amitriptyline, clomipramine and neuroleptics in phenotyped patients. Pharmacol. Res. 31:347–353.
von Bahr, C., Movin, G., Nordin, C., Lidén, A., Hammarlund-Udenaes, M., Hedberg, A., Ring, H., and Sjövist, F. (1991). Plasma levels of thioridazine and metabolites are influenced by the debrisoquin hydroxylation phenotype. Clin. Pharmacol. Ther. 49:234–240.
Wang, S. L., Huang, J. D., Lai, M. D., Liu, B. H., and Lai, M. L. (1993). Molecular basis of genetic variation in debrisoquin hydroxylation in Chinese subjects: Polymorphism in RFLP and DNA sequence of CYP2D6. Clin. Pharmacol. Ther. 53:410–418.
Wilkinson, G. R., Guengerich, F. P., and Branch, R. A. (1992). Genetic polymorphism of S-mephenytoin hydroxylation. In Kalow, W. (ed.), Pharmacogenetics of Drug Metabolism: International Encyclopedia of Pharmacology and Therapeutics, Pergamon Press, New York, pp. 657–685.
Westermeyer, J. (1991). Fluoxetine-induced tricyclic toxicity and duration: Extent and duration. J. Clin. Pharmacol. 31:388–392.
Wright, J. D., Helsby, N. A., and Ward, S. A. (1995). The role of S-mephenytoin hydroxylase (CYP2C19) in the metabolism of the antimalarial biguanides. Br. J. Clin. Pharmacol. 39:441–444.
Wrighton, S. A., Stevens, J. C., Becker, G. W., and van den Branden, M. (1993). Isolation and characterization of human liver cytochrome P4502C19: Correlation between 2C19 and S-mephenytoin 4′-hydroxylation. Arch. Biochem. Biophys. 306:240–245.
Yasui, N., Otani, K., Kaneko, S., Ohkubo, T., Osanai, T., Ishida, M., Mihara, K., Kondo, T., Sugawara, K., and Fukushima, Y. (1995). Inhibition of trazadone metobolism by thioridazine in humans. Ther. Drug Monit. 17:333–335.
Zhang, Y., Reviriego, J., Lou, Y.-Q., Sjöqvist, F., and Bertilsson, L. (1990). Diazepam metabolism in native Chinese poor and extensive hydroxylators of S-mephenytoin: Interethnic differences in comparison with white subjects. Clin. Pharmacol. Ther. 48:496–502.
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Coutts, R.T., Urichuk, L.J. Polymorphic Cytochromes P450 and Drugs Used in Psychiatry. Cell Mol Neurobiol 19, 325–354 (1999). https://doi.org/10.1023/A:1006945715127
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DOI: https://doi.org/10.1023/A:1006945715127
- drug metabolism
- cytochromes P450
- monooxygenases
- polymorphism
- CYP2D6
- CYP2C19
- CYP2C9
- amino acid sequences
- defective genes
- phenotyping
- genotyping
- ethnic differences in drug metabolism
- CYP enzyme inhibitors
- CYP enzyme substrates
- drug/drug interactions
- poor metabolizers
- extensive metabolizers
- ultrarapid metabolizers
- diet
- age
- cancer
- Parkinson's disease
- schizophrenia
- Alzheimer's disease
- epilepsy